--

MEDICAL GRAND ROUNDS

PARKLAND MEMORIAL HOSPITAL

May II, 1967

KIMMELSTIEL - WILSON SYNDROME

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Case No . I

The patient, a 28-year-old Negro male, was a juvenile-type diabet ic with a history of two episodes of diabetic acidosis, one associated with a lung infection. Diabetes was diagnosed at age 15 . He had been on insulin therapy since that time on various doses ranging from 40 to 120 units daily.

At age 26, he was first noted to have diabetic retinopathy . At that time, BUN and urinalysis were normal; blood pressure was 140/90 . He was not seen from that time to the present at which time he presented with a three month history of progressive edema. The edema began in the legs; it was not accompanied by shortness of breath nor orthopnea. However, as the amount of edema increased exertional dyspnea was noted.

Examination disclosed a blood pressure of 160/110, retinopathy and anasarca. La boratory results i ncl uded a BUN of 60, al bumin of 2.4, cholesterol of 368, blood sugar 180 .

Over a three month per i od there were several admissions, primarily because of increased edema . Although measures directed toward d iu resis were moderately successful, he was never edema free. Moreover, there was a continued slow rise in azotemia and the development of metabolic acidosis.

The final admission disclosed signs and symptoms of uremia . The patient's heart which had been slightly enlarged was markedly di fated. 01 iguria was present . The pat ie nt expired some 36 hours after admission.

Case No . 2

The patient w9s a 60- yea r-old Negro man who presented with an indefinite history of mild d ia betes, probably of ten years duration, and marked pitting edema of both lower extremities . On that admission , there was no evidence of cardiomegaly nor conqestive heart failure . There was a m i I e,; dlastol' I c · :hy;pe-r+te'M>s ion 't'o:gether .·¥# i't'h ' f.un'dusco-p ;-c :-ehar:!;ges , ccms i-s+ i n_g of old exudates a nd a n occas ional microaneurysm. There was mild azotemia and the serum albumin concentration varied between 3 . 7 and 4 gm% during that admission . Occasi ona l random urine specime ns showed at most a 2+ reacti on for protein, but many urine samples were negative. On bedrest and a low salt d iet, the patient eventually diuresed losing alI hi s edema and was d ischa rged with a d iagnosis of, in addition to diabetes, idiopathic edema.

Almost one year later the pat i ent was readmitted. At that time, there was no serious impairment of carbohydrate metabol i sm, but again he presented with marked edema without signs of congestive heart fa i lure . At the time of admission, there was aga i n no ev i dence of congest ive heart fa i lure (See Figure I) . Note that a 24- hour ur i ne collected beg i nn i ng the day of admission contained almost 12 grams of prote i n. However, thereafter the 24- hour excretion of prote i n was much lower, usually below the 3.5 to 5 gram per day I imit for the nephrotic range . On admission, the serum albumin concentration was 3.2 g/100 ml and quick ly rose to 4. The serum cholesterol concentrat i on cont i nued t o rise after adm i ssion, but fe l I to 200 mg% by the time of discharge . Frankly evident edema was present for a bout 10 days . Thereafter, he was edema free. He was asymptomatic throughout and manifes ted only mild azotemia, having a BUN varying between 20 and 26 mg%.

Because of the very high urine protein excretion on the day of admission, it was considered poss i ble that this pat ient might from time to time have a mass ive outpouring of protein into the ur i ne resulting in the nephrotic syndrome . Attempts were made therefore to follow the pat ient closely i n the clinic, in an attempt to pi ck up these s porad i c nephrotic episodes. Figure 2 discloses the data obtai ned in following this patient. As can be seen, only

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very few 24-hour urines were obtained during the patient's outpatient course. However, he was instructed to test his urine daily with albumin sticks,and if there was a very positive reaction, to return to the hospital for admission. Approximately 5 weeks after discharge, the patient returned to clinic with marked edema; again without any signs of heart tai lure. He stated that tor the past week his test for urine protein had shown a very strong reaction. However, since he had aclinic appointment he saw no reason tor returning before that date. Note that at the time of admission his serum albumin concentration was just under 2 gm per 100 ml. Note also that the initial 24-hour urine sample contained in excess of 14 grams of protein. Again the massive proteinuria quickly subsided and the serum albumin concentration rather more slowly returned towards normal. Note however, that clinically evident edema persisted even though the serum albumin concentration was within the normal range. Some 18 days after admission, the patient was edema free.

Case No. 3

The patient was a 20-year-old white girl who had been a known diabetic since 18 months of age. For the most part, her control with respect to carbohydrate had been poor, her insulin dosage varying tremendous!~ wei I over 140 units to as low as 50 units of insulin daily. This patient was followed closely as an outpatient in our clinic, and was felt to manifest a continued low grade nephrosis with sudden bursts of massive protein excretion. She maintained ami ld azotemia throughout with diastolic blood pressures in the 90 to 100 mm range. Figure 3 discloses data obtained in this patient during clinic visits over a nine week period. Unfortunately, very few 24-hour urines were collected. However, it can be seen that at least on one occasion there was a massive proteinuria recorded and accompanied by an increase in edema, an abrupt lowering in serum albumin concentration and a later rise in serum cholesterol. Figure 4 depicts her clinical course during a hospitalization that was brought about for an elective ful I mouth extraction. Again 24-hour urine protein _excretion rose and then fel I to very low levels. This resulted in a fal I of serum albumin concentration to 2.0 gm per cent and was associated with increased clinical edema . Thus, a pattern similar to the patient in Case No.2 is demonstrated.

Case No. 4

The patient was a 58-year-old white man who had diabetes of the adult onset type of nine years duration. At the time of admission, he was markedly edematous, dyspneic and orthoptic; blood pressure was 160/110. There was cardiomegaly and a right pleural effusion. Venous pressure was 22 ~m of water and circulation time was 18 seconds. The serum albumin was 3.6 gm%. On the day following admission, a 24-hour urine disclosed an excretion of 8 . 7 grams of protein. Subsequently, several urines for protein disclosed a 24-hour urine of less than 2.5 gms per day. The patient had modest azotemia with a BUN varying between 25 and 30 mg% and a creatinine varying between I .5 mg% and 2.0 mg% . He was treated with a low salt diet, bed rest and diuretics and had an uneventful recovery.

TABLE

MorPhology of Glomerular Lesions

I . Discrete Nodular Lesions- The true Kimmelstiei-Wi lson lesion- nearly specific.

2 . Diffuse Lesion- Mesangial prol iteration- not specific .

3. Exudative Lesion- So-cal led fibrin caps and capscular drops- non-specific.

Morphology of Vascular Lesions

I. Afferent arteriolosclerosis - non-specific .

2. Efferent arteriolosclerosis- probably specific .

3. Large vessels athersclerosis -non-specific, but very common in diabetic kidneys.

4. Interstitial nephrit is- with round eel I inti ltration- non-specific, but common.

TABLE 2

Incidence of Nephrotjc Syndrome

I ! (. i ( . .. I I ~' \ ' ' I ' ~ ' 0 ( I :· %

Kimmelstiel and Wilson, 1936 ( I) Undetermined

Laipply, Eitzen, and Dutra, 1944 (4) Under 10

Henderson , Sprague, and Wagener, 1947 (5) 6.3

Kimmelstiel and Porter, 1948 (2) 6.6

Mann , Gardner, and Root, 1949 (9) ± 20.0

Rogers and Robbins, 1952 (I I) Under 2.0

Be I I , 1953 (6) 20.0

Lambie and MacFarlane, 1955 (13) 20.0

Gellman, et.§.L, 1959 (20} 26 .0

Hatch, et s..L, I 961 (23) 12.0

REFERENCES

I. Kimmelstiel, P. and C. Wilson. Intercapillary les ions in the glomeruli of the kidney. Amer. J. Patho I . jg:83, 1936.

Presents renal pathology on 8 patients, alI autops ies, 7 had diabetes. Mainly piesents pathology, little clinical data to go on; but from history of long-standing edema­assumes that 7 had nephrotic syndrome. AI I had hypertension. No true assessment of renal funct ion, but states that alI had renal failure.

2. Kimmelstiel, P. and W.B. Porter. lntercapi I lary glomerulosclerosis. New Eng. J. Med. 238:876,908, 1948.

Shows some reluctance to accept the diffuse glomerulosclerotic lesion of Bell. Admits that syndrome may not be complete, but in these patients with severe renal lesions, nephrosis is common.

3. Newburger, R.A. and Peters, J.P. lntercapi I lary glomerulosclerosis; a syndrome of diabetes, hypertension and albuminuria. Arch. Int. Med. 64:1252, 1939.

Presented 4 autopsied cases, 3 of which were considered to have the nephrotic syndrome. Concluded that the syndrome as described by Kimmelstiel was real.

4. Laipply, T.C., Eitzen, 0., and Dutra, F.R. lntercapi I lary glomerulosclerosis. Arch. Int. Med. 74:354, 1944.

In 332 autopsied diabet ics, nephrosis had been present in only 6.3%. An early description of the diffuse glomerular lesion. Noted no relationship to it and severity of clinical picture. Doubted that there was a syndrome.

5 . Henderson, L.L., R.G. Sprague, and H.P. Wagener. lntercapi I lary glomerulosclerosis. Amer. J. Med . .:2,: 131 , 194 7.

The syndrome is often not complete . Noted a "high incidence" of cardiac decompensation in those patients with IGS. 33% as opposed to I 1%. In only 4 of 29 patients was the nephrotic syndrome present. Albuminuria present in 95% of 29 . "Serum proteins-there were only four determinations of total serum proteins among the cases of inter­capi I lary glomerulosclerosis, the values being 6.7, 6.6, 5 . 5 and 4.3 gm per 100 cc of serum. These meager data, and the fact that this determination was not made more frequently, suggest that hypoproteinemia of marked degree is probably not a common manifestation of intercapi I lary glomerulosclerosis."

6. Bel I, E.T. Renal vascular disease in Diabetes Mel I itus. Diabetes g:376, 1953.

A study of 1465 autopsies in diabetic patients. First strong emphasis of the diagnostic importance of sclerosis of the efferent arteriole. "There is, however, no close correlation between the degree of edema and the severity of the hypoproteinemia."

7. Hal I, G.F.M. The significance of atheroma of the renal arteries in Kimmelstiei-Wi lson's syndrome. J. Pathol . and Bacterial. 64:103, 1952.

The author attempts to show, on the basis of autopsy material, that atheromatous disease of the renal arteries and of the larger arteries within the kidney is responsible

REFERENCES (2)

for the severe clinical forms of K-W syndrome.

8. Hal I G.F .M. Factors in the etiology of d iabet ic glome r ulosc leros is . Quart . J . Med. £1:385' 1952 .

Report on autopsy f i ndings in 120 diabetic patients. Incidence of glomerulosclerosis was 37.5% . No significant new data. No mention of the inc idence of nephrosis.

9. Mann, G.V., Gardner, C. , and Root , H.F. Clinical man i festations of intercapi I lary glomerulosclerosis in diabetes mel I itus. Am . J . Med. 1 :3, 1949.

Concludes from the s tudy of 83 diabet ics wi th "renal di sease" that the K- W synd rome is a true clinica l entity. Of these 83 patients with mi xed renal disease, 20.5% were said to have nephrosis.

10 . Wi I son, J .L. , Root, H.F , , and Marble , A. Di a betic neph ropathy . New Eng . J . Med. 245:513, 1951 .

II.

Believes the term "diabetic neph ropa thy" better than K- W syndrome or ICGS. Notes that a high per centage of cases have acute and ch ronic pyelonephritis at aut opsy. Many have arthersc lerotic changes . Most have arteriolosclerosis .

Rogers, J. and S .L. Robbins . lntercapi I lary Glomeruloscleros is : pathologic study. I , Specificity of the clinical syndrome. I ~. : 6R8, 1952 .

A clinica l and Amer . J. Med.

Clinical - patholog i c correlation (autopsy material) in 229 diabetics . Only 4 had nephrotic syndrome (basis of this diagnosis not described). From clinical diagnosis 57% were not correctly diagnosed as having the pathologic les ion . Also 32% were d i agnosed as having lesion on c lin i cal grounds when i t was a bse nt patholog ica lly.

12 . Rogers, J., Robbins, S .L . and H. Jeghers. lntercap i I lary glomerulosc lerosis; a cl i nical and patho I og i c study: I I • A c I in i ca I study of I 00 anatom i ca I I y proven cases. Amer. J. Med. ~: 692, 1952.

One hundred d iabetic patients with a pathologic diagnosis of l OGS we r e compa red with 176 diabet ic patients not having this les ion. Concluded t hat ma ny , i f not most , of patients with !CGS do not have the classic syndrome. The classi c syndrome is occasionally

se-en.· i ;,. , d'i abet l cs t hat do not have I CGS. However, t he c I i n i ca I di agnosis of t he patho I og i c lesion i s mor e often mi s sed than incorrectly diagnosed.

13. Lambie, A.T. and A. MacFarlane . A clinico- pathological study of diabetic glomerulosclero­sclerosis . Quart . J . Med . 24 : 125, 1955 .

A patholog i c study of 120 diabetic patients that came to autopsy . 46% had renal lesion . A total of I I patients were diagnosed as having the nephrotic syndrome . In these I I patients - urine albumins given as gms /li t er only va r ied from I to 12 . Serum albumin concentration in alI but one case over 3 .0 gms% . Four of these patients died of "uremia." Massive albuminuria was associated principally with the "exudative lesion . "

REFERENCES (3)

14. Epstein, F.H. and Zupa, V.G. Clinical correlates of the Kimmelstiei-Wi lson lesion. New Eng. J. Med. 254:896, 1956.

Study of 137 autopsied cases. .serum albumin below 3.0 gm%. edema present.

Thirty-seven had nodular lesions. Twenty-three had Thirty had edema; however, 31 had signs of CHF when

15. Zubrod, C.G., Enersole, S.L., and Dana, G.W. Amelioration of diabetes and striking variety of acidosis in patients with Kimmelstiei-Wi lson lesions. New Eng. J. Med. 245:518, 1951.

Reviewed the clinical history of 190 post mortem diabetics and concluded that by some means, K-W lesions lower the insulin requirement in these patients.

16. Runyan, J.W. Jr., Hurwitz, D. and Robins, S.L. Effect of Kimmelstiei-Wi lson syndrome on insulin requirements in diabetics. New Eng. J. Med. 252:388, 1955.

Concluded that insulin dose tended to be lower in those patients that had the "ful 1-blown K-W Syndrome" and thought this was due to a decreased food intake.

17. Marble, A. Diabetic nephropathy. In Djseases of the Kidney, Eds., Strauss, M.S. and Welt, L.G. Little, Brown and Co., 1963. pp. 620-626.

A review stressing the incompleteness of the K-W syndrome.

18. Heptinstal I, R.H. Pathology of the Kjdney. Little, Brown and Co., 1966. pp 465-490.

i

Stresses the point that pathologically lesions previously thought to be due to chronic rena I infection ( pye I onephr it is) are, for the most part, the resu It of vascu I ar disease. BeJ ieves that term "K-W syndrome" should be dropped.

19 . Thomsen, A.G. The significance of renal biopsy for the diagnosis of pyelonephritis in diabetic patients. In Ciba Foundation Symposium on Renal Biopsy, Eds., Wolstenholme, G.E.W. and Cameron, M.P. Little, Brown and Co., 1961, Boston, p 281.

Concludes that moderate to severe insterstitial inti ltration with round eel Is, and periglomerular fibrosis were non-specific changes that could be the result of vascular disease.

20. Gellman, D.D., Pi rani, C.L ., Soothi II, J.F ., Muehrche, R.C. and Kark, R.M. Diabetic nephropathy: A clinical and pathologic study based on renal biopsies. Medicine, 38:321,1959.

21. Kark, R.M. and Gellman, D.D. Renal disease in diabetes. In Diabetes, Ed . R.H. Wi I Iiams, P.B. Hoeber, New York, 1960, p 569.

22. Gellman, D., Pi rani, C.L., Soothi II, S.M., Muehrche, R.C., Maduros, W., and Kark, R.M. Structure and function in diabetic nephropathy. Diabetes a:251, 1959.

REFERENCES (4}

I. Most common les ion ( biopsy) was d i ffuse d iabetic glomerulosclerosis (75% of 53 selected pat ients ).

2. Nodular les ions seen in 48%- i s specif i c .

3. Class i ca l patho logy of acute and chronic pyelonephr i tis not seen in this series .

4 . Severity of the nod u lar les ion did not correlate with the clinical status.

5. Sever i ty of the d i ffuse les ion d id correlate with the clinical picture .

6 . Nodular lesion does not cause nephros i s.

7 . The term"K-W Syndrome" should be dropped.

23. Hatch, F.E., Watt, M.F., Kramer, N.C., Parrish, A.E., and Howe, J .S. Diabetic glomeru­. loscleros is: A long-term follow-up study based on renal biops ies. Am. J. Med •

..2J_: 2 I 6 , I 96 I •

Only report wi th good cr iter ia for diagnosing nephrotic syndrome. On this basis, 5 of 41 patients had nephros is, but 19 other patients were poss ib le nephrot ics . Noted edema present with relatively high serum albumin concentrat i on. Also thought cl i ni cal state correlated best wi th the severity of the diffuse, but not nodular glomerular lesion .

24. Shap i ro, A.P., Perez -Stable, E., Moutsos, S .E. Coex istence of renal arterial hypertension and ~iabetes mel litus. J. Amer . Med. Assoc . 192:813, 1965.

Patients found to have ''renal artery hypert ension» were tested for diabetes. Of 55 patients, 24 were cons idered d iabet ic. Suggested that hypertension in diabet i cs

_ may be more reasonably asc ri bed to renal artery disease (pressor hypertension} than K- W les ions i n the kidney .

25. Osawa, G., Kimmelstiel, P o, and Sei I ing, Vo Thickness of glomerular basement membranes. Am. J. Cli n. Path. 45:7, 1966.

From normal adult biopsy and autopsy mater ia l the mean width of BM was found to be 3146 ± 983 ~. A maximum mean width of 5112 ~was st i I I considered normal. No variation with sex or age o

26. Kimmelst iel, P., Osawa, G., Beres, Jo Glomerular basement membrane in diabetics. Am. J. Clin . Pathol o 45 :21, 1966 .

Width of 5373 ± 2280 ~with nodules . · Width of 3293 ± 1260 ~w i thout nodules. Concludes that thicken i ng of G.BoM . is not an early lesion in diabetes .

27. Harrington, A.R., Hare, H.G., Chambers, W.N., and Valt i n, H. Nodula r glomerulosclerosis suspected during I ife in a patient without demonstrable diabetes mel I itus . New Eng. Jo Med o 275:206, 1966.

No glucose i ntolerance could be detected in this pat ient with a family history of diabetes, who clin ically manifested nephrosis, hypertension, and renal failure . Renal pathology class i cal for diabetes.

REFERENCES (5)

28 . Squire, J .R. , Bla i ney, J .D. , and Hardw icke, J . The nephrot ic syndrome . Brit. Med. Bull . .U.:43 , 1957.

An excel lent review of the pathophysiology of the nephrotic syndrome .

29 . Kaitz, A.L. Albumin metabol i sm in neph roti c adults . J. Lab. Cl in . Med. 53:186, 1959.

30.

31 •

In overt nephrotics, showed that albumin catabolism was increased.

Wyers, P. J.H., and Van Munster, P. J. J . in normal and nehprotic subjects .

Disappearance of Evans blue dye from blood J. Lab . Cl i n . Med. 58:375, 1961.

Showed that Evans blue dye appeared i n ur i ne of nephrotic pat ients unassociated with protein. Concluded that there was a marked catabolism of protein i n the kidney of filtered protein .

Katz, J . , Sellers, A.L . , and Bonorris, G. catabolism i n exper imental neph ros is.

Effect of nephrectomy on plasma albumin J . Lab . Clin . Med . 63 ~ 680, 1964.

Shows that album i n catabo l ism is reduced by removal of kidneys i n nephrotic rats .

32 . Nussle, D., Barandun, S., and Witsch i , H.P . Pertes digestives de proteines et syndrome nephrotique . In Plasma Prote i ns and Gastrointestinal Tract in Health and Disease . Wi II iams and Wi lk i ns , 1963, Balt imore, p 180 .

Descr i bes 4 ch i ldren wi th nephroti c syndrome that have marked loss of albumin into gastrointestinal tract.

33. Yamuch i , H. and Hopper, J. Hypovolemic shock and hypotens ion as a complication in the Nephrotic Syndrome. Ann. Int . Med. 60 :242, 1964.

" Some edema may be necessary to prevent orthostatic hypctension in nephrotic patients.

34. Youmans, W.B . Mecha ni sm of hi gh output c i rculator y failure , Ann . Int. Med. !1: 747, 1954.

35.

A discussion of venous congest ive states.

Sims, E.A.H., MacKay, B.R . , and Sh i ra i , T. diabetes mel I itus to idiopathic edema .

The relation of capi I lary ang iopathy and Ann. Int . Med . 63~972, 1965.

Ascribes edema to increased thickened basement membranes of muscle capi I laries (thus increased permeability) and finds that most patients are either diabetic or have a family hi story. Not entirely conv i ncing .

36. Rector, F .C., Brunner, F .P . , Seldin , D.W . Mechanism of glomerulotubular balance . I . Effect of aortic constriction and elevated ureteropelvic pressure on glomerular filtration rate, fractional reabsorption, transit t ime, and tubular size in the proximal tubule of the rat . J. Clin . Invest. ~: 590 , 1966.

REFERENCES (6)

Brunner, F.P., Rector, F.C., and Seldin, D.W. Mechanism of glomerulotubu.lar balance . I I . Regulation of proximal tubu lar reabsorption by tubular volume, as studied by stopped-flow microperfusion . J . Clin. Invest . ±2:603, 1966.

CLINICAL COU RSE - K-W we. 60 yr. old

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Admission DAYS

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